Seth Harris
Director and Senior Principal Scientist (Technology), Computational Structural Biology
"Scientific discoveries help drive progress, particularly towards sustainability. It is exciting to work where you can imagine each day might be the day where you help design or contribute to a new therapeutic that could have world-wide impact, or a new class of antibiotic that might be a first for the whole human race in over 50 years!"
I study protein architecture and function as a window into fundamental and mechanistic understanding of biology and disease. My academic research focused on structural aspects of papillomavirus transcription and heat shock protein 90 (Hsp90). I continued with structure-based drug design at Roche Palo Alto, contributing to diverse discovery projects including hepatitis C virus (HCV) and human immunodeficiency virus (HIV) research. Since 2009 I have been in the Structural Biology group at Genentech, enjoying an unparalleled breadth of topics and collaborations, unified in the focus to aid patients with new therapeutics. To wit, I work on advanced small molecule and biologic discovery projects in neurodegeneration, oncology, angiogenesis, metabolism, cancer immunotherapy, and infectious diseases. In addition, we also explore fundamental research questions, exemplified by my group’s recent elucidation of a ternary complex structure of a deubiquitinase system.
To support these diverse directions I develop computational tools and infrastructure to innovate and facilitate our capabilities across all projects, both in producing and analyzing protein structures. These include technical aspects such as using acoustic liquid transfer to set up nanoliter-scale crystallization trials, as well as software tools and database interfaces to navigate our ever-expanding structural and functional datasets.
Postdoctoral Mentor
Genentech’s postdoctoral program provides an incredible platform of resources and collaborative scientific context to explore innovative research directions, truly bridging industry and academic foci. Our group is expanding involvement with highly engaged researchers who bring their own unique ideas and directions pertinent to our pipeline work, but with publication-oriented, broader implications and understanding of novel biology. We are aiming to combine structural biology, including state-of-the-art crystallography and electron microscopy techniques, with informatics and biochemical analyses to study larger multi-subunit protein complexes in the ubiquitin pathway. These structure:function discoveries will provide insight into regulation and prospective for therapeutic intervention. We are excited to initiate this project, motivated by the potential inherent in the available scientific resources and expertise at Genentech that creates fertile ground for inquisitive research to support and aid in the development of new careers and discovery in these areas.
Featured Publication
Structural Insights into WD-Repeat 48 Activation of Ubiquitin-Specific Protease 46
Structure (London, England : 1993), 2015, ISSN: 0969-2126
Yin J, Schoeffler AJ, Wickliffe K, Newton K, Starovasnik MA, Dueber EC, Harris SF.
My research in structural biology spans neurobiology, angiogenesis, oncology, epigenetics, cancer immunology, infectious diseases and beyond. We collaborate with diverse colleagues to enable complementary studies of structure and function beyond our crystallography focus, including cryo electron microscopy, NMR, and biophysical techniques. On the technical front, I work to develop tools that can streamline and help us understand cohorts of numerous structures and their conformational variations. My group has helped develop the implementation of acoustic liquid transfer technologies in aid of protein crystallization, allowing nanoliter-scale trials efficiently to identify crystallization conditions.
With this as a platform, we work with medicinal and computational chemists in rational drug design, solving co-crystal structures of diverse compounds in complex with target proteins. I chair our biophysics workgroup that focuses on using fragment screening to identify ligand efficient starting molecules for that purpose as well. My interest in computational aspects of structural datasets also led to our contribution of a large cohort of kinase structures to the inaugural public blind challenge event organized by the Drug Design Data Resource (D3R) group.
On the large molecule front, my group determines antibody:antigen complexes to elucidate the nature of epitope recognition and how to improve, for instance, a dual-acting antibody fragment that can potently recognize two distinct antigens. My lab also recently determined novel structures of large protein complexes involved in deubiquitination, establishing a foundation for further investigations via postdoctoral research within my group.
- University of California, San Francisco, Helen Hay Whitney Postdoctoral Fellow – 1999-2004
- University of California, Berkeley, Ph.D. – 1994-1999
- Yale University, B.S. Molecular Biophysics & Biochemistry and Studies in the Environment. – 1988-1992
- Helen Hay Whitney Postdoctoral Fellow – 1999-2004
- Poster Prizes, Advanced Light Source and Stanford Synchrotron Radiation Laboratory Users’ Meetings – 1998